Unilaterally acylated diamines and process of making same



Patented Nov. 8, 1932 UNITED s'r 'ras PATENT OFFICE m HABTIANN, HANS KAEGI, AND HANS ISLER, OI BASEL, SWITZERLAND, ASSIGNOBB TO J3EE rm]: SOCIETY OI CHEMICAL INDUSTRY IN BASLE, OF BASEII, SWITZER- LAND UNILA'I'EiB-ALLY AGYLAIED DIAIINES AND PROCESS OI MAKING SAME Io Drawing. Application fled December 18, 1987, Serial No. 240,618, and in Switzerland and Germany November 7, 1827.

The present invention relates to the manufacture of unilaterally acylated diamines. It comprises the process of making these compounds, as well as the new products themselves.

It has been found that unilaterally acylated diamines of the general formula A representing an alkylene radical containing at least two carbon atoms, R meaning any hydrogenated or non-hydrogenated heterocyclic radical and R and R" meaning hydrogen or any monovalent radical, may be obtained by causing a heterocyclic compound of the formula: R.CO.X

R meaning any hydrogenated or non-hydroenated heteroc clic residue, and X meaning %or instance 0 ,halogen or 0B,, R being a monovalent alkyl radical, to react, if necessary, in the presence of an acid binding agent, with an alkylenediamine of the formula:

in R' \N-AN/ 11 a A representing an alkylene radical containing at least two carbon atoms, and R and R" meaning hydrogen or monovalent radicals. In the case Where R and R are alkyl radicals the possibility of course is included that they may be directly linked together by their carbon atoms, as for instance in w-amino-N-ethylpiperidine of the formula CHa-CH:

CHrCH:

For the acylation there may be used either hydrogenated or non-hydrogenated heterocyclic carboxylic acids, or the halides or esters thereof. By heterocyclic carboxylic acid there are to be understood those containing for instance a pyridine, a quinoline, an isoquinoline, an acridine, a pyrazolone, or another heterocyclic ring. According to the invention the diamines acylated by non-hydrogenated heterocyclic carboxylic acids may be subsequently reduced if desired.

The bases produced by the invention form with acids salts soluable in water. The are characterized by the high degree of t erapeutic activity. For example, 2-phenyl-4- quinolinecarboxylic acid diethylethylenediamine has the effect of depressing the blood pressure while tetrahydro-l-quinolinecarboxylic acid diethylethylenediamine has a pronounced efl'ect upon the heart. The products therefore find application in therapy.

The following examples illustrate the invention, the parts being by weight Example 1 150 parts of 2-phenyl-4quinolinecarboxylic I acid and 75 parts of unsymmetrical diethylethylenediamine are heated together in an autoclave at 180200 C. The contents of the autoclave are dissolved in alcohol, the solution filtered and mixed with water until it begins to become turbid. The 2-phenyl-4-quinolinecarboxylic acid diethylethylenediamine of the formula 00. NH. CH1. CH N(C:Hl)l

tains 2 molecules of water of crystallization. Example 2 C0. NH. CH:- CHQ. NH:

in the form of colorless crystals of melting point 124-125 C. This compound is sparingl soluble in water and ether; more freely solu le in benzene and insoluble in petroleum ether.

The dihydrochloride is very easily soluble in water.

Example 3 4-quinolinecarboxylic acid and 116 parts of unsymmetrical diethylethylenediamine are heated together at 200-220 C. The product is dissolved in ether and the solution is washed with water. From the ethereal solution a base, which is sparingly soluble in ether, crystallizes on standing in the form of fine slender needles which melt at 132 C. From the concentrated mother liquor there may be obtained another base easily soluble in ether and crystallizing in large glassy prisms of melting point 97.5 C. Both bases are apparently isomeric 2-phenyl-1 :2: 3 4-tetrahydro-4- quinolinecarboxylic acid-diethylethylenediamines of the formula H 00. NH. on. era. moan),

The bihydrochloride of the first base melts at 5 192 C. while decomposing; that of the second at 225 C. while decomposing.

Both bases may also be obtained by reducing the compound made as described in Ex ample 1.

Example 4 253 parts of 2-phenyl-1: 2: 3 4-tetrahydro- 4-quinolinecarboxylic acid and 144 parts of triethylethylenediamine areheated for some time to over 200 C. The product thus ob- 253 parts of 2-phenyl-1:2z3z i-tetrahydro- 0.NH.CHa.CH:.N c

remains as a thick oil.

The salts of the base are easily soluble in water.

Ewample 5 Equal parts of 2-ethoxy-4-quinoline-carboxy lic acld-ethylester and unsymmetrical diethylethylenediamine are heated in the oil bath to 130 C. The product is dissolved in ether, washed with water and neutralized by means of an acid. The base is precipitated by addition of sodium carbonate and is ex-' tracted by ether. The residue from the ether is re-crystallized from petroleum ether. The 2-ethoxy-4-quinolinecarboxylic acid diethylethylenediamine of the formula CaHl N forms colourless crystals melting at 97 C. With acids it yields salts easily soluble in water.

Example 6 drobromide of 3-pyridinecarboxylic acidpiperidine-N-ethylamine of the formula H -CH is crystallized .from alcohol and re-crystallized from ethyl-acetate. It melts at 182- 183 C. and dissolves easily in water.

Example 7 62 parts of 2-n-hexyl-B-benzo- -quinolinecarboxylic acid (Berichte 27, page 2022) and 100 parts of unsymmetrical diethylethylenediamine are heated together in an autoclave to 230250 C. The product is dissolved in ether; the solution is washed and evaporated to dryness. The residue is dissolved in some acetone and mixed with alcoholic hydrochloric acid. The bihydrochloride of 2-n-hexyl-p-benzo- -quinoline-car-- boxylic acid-diethylethylenediamine of the .formula.

oomncmcmnwium (crimes.

is precipitated in the form of a bright yellozvvislgJ crystalline powder which melts at 274 2 5 Example 8 Q-acridinecarboxylic acid (meso-acridinecarboxylic acid;l is converted into its chloride by means of p osphorus pentachloride and then mixed in toluene solution with an excess of unsymmetrical diethylethylenediamine. The mixture is extracted with dilute acid, the acid solution mixed with sodium carbonate in excess and the base extracted by means of ether. The 9 acridinecarboxylic acid-diethylethylenediamine of the formula is purified by crystallization from benzene and forms pale yellow laminae which melt at 106 C. It is freely soluble in ether and alcohol and sparingly soluble in petroleum ether and benzene.

The salts of the base are easily soluble in water. 7

Example .9

2 parts of 122:3:4-tetrahydro-9-acridinecarboxylic acid chloride (made from the acid by action of phosphorus pentachloride) are dissolved in toluene and the solution added drop by drop to a solution of 3 parts of triethylethylenediamine. The product is extracted by shaking with dilute acid, precipi tated from the acid solution by means of sodium carbonate and extracted by ether. After the ether has been distilled there remains the 1 2:3 :4-tetrahydro-9-acridinecarboxylic acid triethylethylenediamine of the formula c on cmcmmcm'),

H: in the form of a yellow viscid oil of boiling point 189191 C. at 0.015 mm. pressure. It

is soluble freely in organic solvents, with the exceptlon of petroleum ether.

Both the hydrochioride and the acetate are freely soluble in water.

Example 10 11.6 parts of l-phenyl 5 pirazolone 3 carbox lic acid-ethylester are eated in the oil bat with 12 parts of unsymmetrical dieth lethylenediamine at 155-160 C. After coo 'ng, the condensation product crystallizes in slender white needles, which are washed with water.

The hydrochloride of 1-phenyl-5-pyrazolone-3-carbox lic amine of the ormula N 06 \N mo li-ooxmcmcmriwm.) 2

may be re-crystallized from alcohol and forms white crystals easily soluble in water and of melting point 220 C.

acid-diethylethylenediacid. The oxylate of the 5:6-methylenedioxy-8-phenyl-2 3-dihydro-2-isoquinolinecarboxylic acid-diethylethylenediamine of the formula is recipitate as a yellow crystalline owder. Ai ser recrystallization from alco ol the product melts at 206207 C.

All salts are colored strongly yellow. The following table shows certain other bases which may be obtained according to the invention 1. 2-phenyl-4-quinollnecarbox- Hydrobromlde: melting yllc 2 C.

acld plperldlne-N- point 10 etliylamlne 2. 2-phcnyl-6ethoxy4-qulno- ,Base: colorless crystals linecarboxyllc acld-dimelting point ethylethylcnedlamlne 128 C.

3. 4-quinol lnccarboxyllc acld- Base: olly.

piperullne-N-ethylamlue 4. 3-qumollnecarhoxyllc acld- Base: colorless crystals, diethylethylenediumine boiling point 245 C. at

4 mm. pressure. Base: colorless crystals, v

melting point 94 C.

. 2-methqxy-4-quinollnecarboxylicacid-dlethylethylenediamine 6. 2z3-tlblghefiyl4-p lixioglnei Base; icolorlesi; needles.

car xyc ac e metn n 16- ethylenediamlne y 147 C? m t lac Base: colorless crystals, melting point 98-99 0.

Base: oily. boiling int 187-188 C. at .007 mm. pressure.

7. 2 F phenylethyl-4 uinolnecarboxylic aci -diethylcthylenedlamine 8. 2 q phenylethyl-4- nine- 1 ne-carboxylic ac d-triethylethylenediamine 9. 2-styryl-4-quinolinecarbox- Base: colorless crystals, 6 ylic acid-diethylethylmelting oint 98-99 C.

cnedlamine Hydroch orlde: meltin; point 122' C. 10. Tetrahydro-9-acridlne-car- Bale colorless crystals, boxylic acid diethyl melting point 97-98 C. ethylenediamlne 11. 9 acridinecarboxyllc acid- Base yellowish crystals, die thylpentamethyiene melt diamine.

R.CO.X

R meaning any hydrogenated or non-hydrogenated heterocyclic radical containing nitron in the heterocyclic nucleus, and X mean- 20 mg OH, halogen or B,, R being a monovalent alkyl radical, to react with an alkylene diamine of the formula RI RI! \NA-N/ H/ \RII wherein A represents an alkylene radical containing at least two carbon atoms, R" and'R" stand for hydrogen or ethyl, both R" may also so stand for an alkylene chain to form a piperidine ring, which products form with acids salts soluble in water. 2. A process for the manufacture of unilaterally acylated diamines by causing a hetero- 85 cyclic compound of the formula R.CO.X

R meaning any hydrogenated or non-hydroenated heterocyclic radical containing a pyridine nucleus and X meaning OH, halogen or OR R being a monovalent a to Iieact with an alkylene diamine of the formu a RI RI! \NAN/ H/ \R wherein A represents an alkylene radical containing at least two carbon atoms, R and R" stand for hydrogen or ethyl, both R may also stand for an alkylene chain to form a pi eridine rin which products form with acids salts solu le in water.

3. A process for the manufacture of unilaterally acylated diamines by causing a heterocyclic compound of the formula R.CO.X

lkyl radical,-

wherein R and R" stand for hydro en or ethyl, both B" may also stand for an al lene chain to form a piggridine rin which products form with aci salts solu le in water.

4. A process for the manufacture of unilaterally acylated diamines by causing a heterocyclic compound of theformula R- meaning any h drogenated or non-hydronated heterocyc ic radical containin a pyridine nucleus and X meaning OH, alogen or 0R R being a monovalent alkyl radical, to react with an alkylene diamine of the formula i n' c,m

N-omcmN 11 cm wherein R stands for hydrogen or ethyl, WlllCl'i products form with acids salts soluble in water.

5. As new products unilaterally acylated diamines of the formula RP RI! wherein R means any hydrogenated or nonhydrogenated heterocyclic radical containing a pyridine nucleus, A represents an alkylene radical containing at least two carbon atoms, R and R" stand for hydrogen or ethyl, both B" may also stand for an alkylene chain to form a piperidine ring, which products form with acids salts soluble in water.

7. As new products unilaterally acylated diamines of the formula wherein R means any hydrogenated or nonhydrogenated heterocyclic radical containing a pyridine nucleus, R and R" stand for hydrogen or ethyl, both R" may also stand for an alkylene chain to form a piperidine ring,

which products form with acids salts soluble in water.

lene c ain to form a piperidine ring,

8. As new products unilaterally acylated diannnes of the formula N-CHz-CHr-N R-CO C2115 wherein R means any hydrogenated or nonhydrogzenated heterooyclic radical containing a pyridine nucleus and R stands for hydrogen or ethyl, which products form with acids salts soluble in water.

In witness whereof we have hereunto signed our names this 5th day of December,

MAX HARTMANN. HANS KAEGI. HANS ISLER. 

